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Clarke studied filmmaking with Hans Richter at the City College of New York after making In Paris Parks (1954). In 1955 she became a member of the Independent Filmmakers of America. She became part of a circle of independent filmmakers in Greenwich Village such as Maya Deren, Stan Brakhage, and Jonas Mekas.
Her 1963 film was The Cool World & Robert Frost: A Lover's Quarrel with the World.
Clarke also directed a 90-minute Cinéma vérité interview with a black homosexual titled Portrait of Jason (1967), which has been called an insightful exploration of one "persons character while it simultaneously addresses the range and limitations of cinema-verité style." -- Lauren Rabinovitz. She created the 90-minute film from twelve hours of interview footage. It was distributed by the Film-Makers Distribution Center, which was co-founded by Clarke in 1966, closing in 1970 due to a lack of funds.
In 1970, she formed the T.P. Videospace Troupe, a loose collective working in experimental video and theater.